SIRT5‐Mediated Desuccinylation of RAB7A Protects Against Cadmium‐Induced Alzheimer's Disease‐Like Pathology by Restoring Autophagic Flux

• DOI: 10.1002/advs.202402030
• Publication Date: 2024-06-05T12:23:50Z
• Authors: Ping Deng; Tengfei Fan; Peng Gao; Yongchun Peng; Min Li; Jingdian Li; Mingke Qin; Rongrong Hao; Liting Wang; Min Li; Lei Zhang; Chunhai Chen; Mindi He; Yonghui Lu; Qinlong Ma; Yan Luo; Li Tian; Jia Xie; Mengyan Chen; Shangcheng Xu; Zhou Zhou; Zhengping Yu; Huifeng Pi
• Keywords: sirt5; Male; autophagy; 0303 health sciences; cadmium; Science; Q; rab7 GTP-Binding Proteins; Mice; Disease Models, Animal; 03 medical and health sciences; Alzheimer Disease; rab GTP-Binding Proteins; rab7a; Autophagy; alzheimer's disease; Animals; Sirtuins; Humans; Research Article; Cadmium

Cadmium (Cd) is a neurotoxic contaminant that induces cognitive decline similar to observed in Alzheimer's disease (AD). Autophagic flux dysfunction attributed the pathogenesis of AD, and this study aimed investigate effect autophagy on environmental Cd-induced AD progression underlying mechanism. Here, Cd exposure inhibited autophagosome-lysosome fusion impaired lysosomal function, leading defects autophagic clearance then APP accumulation nerve cell death. Proteomic analysis coupled with Ingenuity Pathway Analysis (IPA) identified SIRT5 as an essential molecular target Cd-impaired flux. Mechanistically, hampered expression SIRT5, thus increasing succinylation RAB7A at lysine 31 inhibiting activity, which contributed blockade. Importantly, overexpression led restoration blockade, alleviation Aβ deposition memory deficits, desuccinylation Cd-exposed FAD